Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. The current protocol consists of 3 primary studies designed to address 3 major questions: Study 1 (Rapid improvement research in unipolar depression) OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist;onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. There is now an ongoing study with subunit selective NMDA antagonists (NR2A and NR2B). Study 2 (Rapid improvement research in bipolar depression) Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? The efficacy component of the study is completed and the data are being analyzed. The study remains open for active recruitment as more subjects are required to complete the neurophysiological (MEG, PSG, PET substudies) in search of biomarkers of response. Study 3 (Rapid and sustained improvement research in unipolar depression) Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients ages 18 to 65 years with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine are then randomized to receive in a double-blind study with either riluzole or placebo to determine if the rapid response obtained can be sustained. The study is still actively recruiting study participants. The results from this study are not yet available because the study has not yet been completed. Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression. Other aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), and 3) to test other glutamatergic modulators in mood disorders that target NR2A and NR2B. Results in the past year: 1) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg). Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes;these decreases remained significant through the first 4 hours postinfusion (P <.001). Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. 2) Rapid antidepressant effects in treatment-resistant bipolar depression. In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist. 3) Acute changes in mood and sleep slow waves induced by a single infusion of an NMDA antagonist in Treatment-Resistant Major Depression We examined the possible link between slow waves, sensitive markers of sleep pressure, and NMDA channel blockade as a biomarker of response to ketamine. The effects of a single ketamine infusion followed by double-blind administration of either placebo or riluzole on sleep EEG and mood were studied in 30 patients with treatment-resistant MDD. Montgomery-sberg Depression Rating Scale (MADRS) scores decreased significantly (30%) and rapidly following ketamine infusion. Compared to baseline, SWA significantly increased during the first NREM sleep episode after ketamine infusion. Furthermore, the occurrence of high amplitude waves significantly increased during the first NREM sleep episode, consistent with a net increase in synaptic efficacy. Mood effects correlated with the effects on high amplitude slow waves, consistent with an association between behavioral changes and changes at the synaptic level. Taken together, the results suggest that strengthening of cortico-cortical connections, reflected by increased SWA and slow wave amplitude, may be the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. 4) An investigation of Amino Acid Neurotransmitters as potential predictors of clinical improvement to ketamine in depression Dysfunction of amino acid neurotransmitter systems plays a major role in the pathophysiology of major depressive disorder (MDD). Accumulating evidence shows that the NMDA antagonist ketamine produces a rapid antidepressant response in patients with treatment-resistant MDD. We herein applied proton magnetic resonance spectroscopy (1H-MRS) to investigate whether prefrontal levels of GABA, glutamate (Glu) and the ratio Glx/Glutamate (a surrogate marker of glutamine) correlate with the decrease in depressive symptoms after a single intravenous infusion of ketamine in patients with MDD. Pretreatment Glx/Glutamate ratio in the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PF)was negatively correlated with clinical improvement in depressive symptoms (rs(11) = -0.572, p <0.05). Pretreatment glutamate levels in the VM-PF were positively correlated with improvement in anxiety symptoms (rs(11) = 0.569, p <0.05). The findings suggest an association between lower Glx/Glutamate ratio and greater clinical improvement by ketamine treatment. Since glutamine is mainly contained in glia, the decreased glutamine found in this study may reflect the reduction in glial cells found in the same regions in post mortem studies of MDD and suggests that glial integrity may be associated with antidepressant responsiveness to ketamine.